Abstract 4414: Arginine metabolism is modulated by androgen signalling and prostate cancer progression

Abstract

Abstract Background: Metabolic reprogramming has been described as one of the hallmarks of cancer. A pathway of promise in prostate cancer management is arginine (Arg) metabolism. Phase 2 clinical trials are underway to study arginine deprivation as a treatment of prostate cancer. However, heterogeneous response has been noted and further studies are needed to better identify prostate tumors most reliant on Arg metabolism. The aim of this study was to investigate if Arg metabolism was associated with androgen signalling and prostate cancer progression from androgen dependent (AD) to androgen independent (AI) phenotype. Methods: The LNCaP prostate cancer cell line was used. Four sets of conditions were tested: LNCaP control, LNCaP in the presence of dihydrotestosterone (DHT), LNCaP with MDV3100 (an AR inhibitor), and a subline of LNCaP (CSS90) which has become AI. MTT viability assay was used to assess cell viability. The Seahorse XF bioenergetics analyzer was used to measure metabolic oxygen consumption. Gas Chromatography and Mass Spectroscopy (GC/MS) was used for metabolomics characterization. Results: LNCaP cells at a baseline are Arg-dependent. Arg starvation led to a 63% decrease in LNCaP cell viability (p<0.0001) in 24hrs. By contrast, the AI CSS90 only demonstrated a 23% decrease in cell viability when depleted of Arg (p<0.01 with Arg control, p<0.001 between LNCaP and CSS90) demonstrating AD cells were much more dependent on exogenous Arg. Enhanced AR signaling with DHT further sensitized cells to arginine depletion with a 73% decrease, and low level AR inhibition decreased response to arginine depletion with only a 21% decrease in cell viability (p<0.001 for all changes). Metabolic characterization by GC/MS demonstrated a 33.8 fold increase in buildup of an arginine metabolism intermediate, ornithine in the CSS90 cells vs LNCaP (p<0.0001) reflecting compensatory ability of the CSS90 cells to endogenously manage Arg metabolism. Modulation of androgen signaling with DHT and MDV3100 demonstrated similar increased reliance of exogenous Arg for AD cells with increased androgen signaling with a 2.2 fold increase in Arg dependent oxygen consumption with DHT and 95% drop with MDV (p<0.0001 for both). Conclusions: Arginine is potentially an important aspect of prostate cancer metabolism. Arg targeted therapies may best be suited towards earlier stage tumors and Arg metabolism characterization may have potential as a biomarker of progression to AI prostate cancer. Citation Format: De-Xue Fu, Hubert Huang, Jee-Hoon Song, Min Xu, Lucy Liu, Mohamad Afnan Khan, Krish Chandrasekaran, Arif Hussain, Ganesh Sriram, Mohummad M. Siddiqui. Arginine metabolism is modulated by androgen signalling and prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4414. doi:10.1158/1538-7445.AM2017-4414